This invention relates to controlling the production of materials expressed by a gene.
It is known to induce cells to produce high levels of desired proteins. In the prior art methods, this induction is controlled by external factors such as the nature of the cloned gene, the temperature, hormones, the nature and amount of nutrients supplied to the cells and the J-like. Such methods have been described in several publications such as for example, "Large-Scale Cell- Culture in Biotechnology" by W.R. Arathoon and J. R. Birch Science v.232, Jun. 13, 1986, pp. 1390-1395.
The prior art methods have the disadvantages of: (1) providing relatively low production; and (2) not being adequately controllable under some circumstances. Thus, where toxic materials are produced, such as the production of a protein that is toxic to the cell that is producing it, the cell. and other cells may be prematurely destroyed by the level of the toxic material in the culture.
Increases in transcription rate have been observed under several circumstances but have not been adapted to practical use in controlling the expression of a gene to provide desired products more effectively.
One such observation showed that increased transcription occurred by accident and was reported without explanation in "Establishment of a Rat Cell-Line Inducible for the Expression of Human Cytomegalovirus Immediate-Early Gene Products by Protein Synthesis Inhibition" Journal of Virology, June, 1986, by Rene Boom et. al., pp. 851-859.
It has also been observed that the tat111 gene product of the retrovirus HIV1 (human immunodeficiency virus 1) has a powerful transactivation expression of genes expressed by the HIVI LTR (long terminal repeat). This observation was described in Rosen, C.A., J.G. Sodroski, and W.A. Haseltine, 1985, "In the human T cell lymphotropic virus type III (HTLV-III/LAV) long terminal repeat", Cell, 41:813-823; Sodroski, J.G., C.A. Rosen, F. Wong-Stall, S.Z. Salahuddin, M. Popovic, S. Arya, R.C. Gallo, and W.A. Haseltine, 1985, "Transacting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat", Science, 227:171-173. This effect has recently been reported to occur subsequently to transcription and the cis element, tar3, that is required, maps to the region -17/+84 in Rosen, C.A., J.G. Sodroski, W.C. Goh, A.I. Dayton, J. Lippke, and W.A. Haseltine, 1986, "Post-transcriptional regulation accounts for the transactivation of the human T-lymphotropic virus type III", Nature, 319:555-559.